PROJECT SUMMARY/ABSTRACT The development of radiation-senstive nanomaterials for in vivo biomedical applications would enable an entirely new class of tools with enhanced detection, diagonosis, and treatment capabilites. Recently, we have investigated a novel class of nanomaterial, X-ray-excitable radioluminescent nanoparticles (RLNPs), also known as nanoscintillators, which are capable of converting X-ray radiation into near infrared (NIR) light. By conjugating these RLNPs with biological targeting agents, such as antibodies, these novel probes can identify molecular signatures a disease or biological processes through imaging. This X-ray-in-NIR-out imaging approach offers several unique advantages over conventional optical imaging including: (1) absence of tissue auto-fluorescent background, leading to better signal-to-noise-ratio (SNR); (2) deep photon penetration of the excitation X-ray source; and (3) the ability to simultaneously multiplex image. In a therapeutic context, these RLNP may serve as energy mediators to optically activate functional ligands for simultaneous multi-therapy delivery when combined with conventional radiation oncology techniques. In this novel strategy, tumor targeted multi-functional RLNPs serve as a link between radiation therapy, photodynamic therapy (PDT), and photochemical internalization (PCI) enhanced drug delivery. We hypothesize that this combined approach possesses several synergies that overcome the individual limitations of each technique. The overall goal of this R35 application is to develop radiation-activated functional nanoparticles for both imaging and therapeutic applications. As a research program development vehicle, this proposal seeks to provide the PI, who is trained in nanotechnology the means to explore this unique nanoscale interaction between materials and biology with the ultimate goal of creating clinically relevant tools. The current application builds logically on the PI's prior work and is focused on applying X-ray stimulated radioluminescence technology toward imaging and radiation therapy. Oregon State University (OSU) and Oregon Health & Science University (OHSU) are ideal settings to undertake this research with strong ties between clinical units at OHSU and basic science and engineering departments at OSU.